A distinct population of B-cells which suppress the progression of and/or enhance the recovery from acquired immune-mediated inflammations has recently been identified and named regulatory B-cells, or “Bregs.” Regulatory B-cells have been shown to play a key role in controlling autoimmunity, and their absence or loss is implicated in the etiology of several autoimmune diseases (see, e.g., Fillatreau et al., Nat. Rev. Immunol., 8: 391-397 (2008), Carter et al., J. Immunol., 186: 5569-5579 (2011), and Ding et al., J. Clin. Invest., 121: 3645-3656 (2011)). Regulatory B-cells appear to control autoimmunity by various mechanisms, including the production of interleukin-10 (IL-10), secondary antigen presentation, and interaction with other immune cells either directly or through secreted antibodies (see, e.g., Mizoguchi et al., J. Immunol., 176: 705-710 (2006)).
Aberrant elevation of regulatory B-cell levels can prevent sterilizing immunity to pathogens, and tumor-induced regulator B-cells have recently been implicated in carcinogenesis (see, e.g., Tadmor et al., Caner Immunol. Immunother., 60: 609-619 (2011), Schioppa et al., Proc. Natl. Acad. Sci. USA, 108: 10662-10667 (2011), and Mauri et al., Trends Immunol., 29: 34-401 (2008)). In particular, regulatory B-cells have been shown to promote breast cancer metastasis by converting resting CD4+ T-cells to T-regulatory cells (Tregs) (see, e.g., Olkhanud et al., Cancer Res., 71: 3505-3515 (2011)).
Regulatory B-cells are a rare B-cell population, and the physiological signals underlying their production are not completely understood. The identification of these signals may allow for the development of therapeutics based on regulatory B-cells to treat a variety of diseases.
Thus, there remains a need for methods of producing and using regulatory B-cells. This invention provides such methods.